Process and autoinjector device for injections with increased patient comfort

ABSTRACT

The invention provides methods and apparatus for injecting a medicine, especially a highly viscous medicine. Conventional methods and apparatus for injecting viscous medicines suffers from a variety of problems such as excessive force during the initial needle insertion and initial injection. In an inventive method, during the initial phase of the injection, energy is stored in a torsion spring that is subsequently released during a later stage of the injection. The present invention also provides for an improved autoinjector; especially via the use of a combination compression and torsion spring that powers the injection through controlling force applied to plunger via a screw flange or nut having pins that ride in a prescribed path down the length of the autoinjector.

RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.15/742,507 filed 6 Jan. 2018 and claims the priority benefit ofPCT/US16/41189 which is incorporated herein by reference and also claimsthe priority benefit of U.S. Provisional Patent Application Ser. No.62/189,134, filed 6 Jul. 2015.

INTRODUCTION

Injections continue to be a very important mode of deliveringmedications. Injections are especially important, yet difficult, forhigh viscosity solutions such as protein compositions. Proteintherapeutics is an emerging class of drug therapy that promises toprovide treatment for a broad range of diseases, such as autoimmunedisorders, cardiovascular diseases, and cancer. Delivery of proteintherapeutics is often challenging because of the high viscosity and thehigh forces needed to push such formulations through a parenteraldevice. Formulations with absolute viscosities above 40-60 centipoise(cP) are very difficult to deliver by conventional spring drivenauto-injectors for multiple reasons. For example, many currentautoinjectors are relatively large or complex. For spring-loadedauto-injectors, a large amount of energy must be stored in the spring toreliably deliver high-viscosity fluids. An auto-injector typicallyoperates by using the spring to push a needle-containing internalcomponent towards the proximal end of the housing of the syringe,thereby extending the needle from the device and inserting it to theproper depth into the patient. Most autoinjectors use the same spring toinsert the needle as is used to deliver the medicament. The injectiondepth depends on stopping a rapidly moving needle in a precise location.Auto-injectors usually contain glass or plastic parts, and excessive andsudden forces could cause the injector and/or syringe to break, due tothe high applied force needed to inject a high-viscosity fluid. Somedrugs can be affected by the violent mixing with air. Also, the soundand vibration associated with the impact can cause patient anxiety,reducing future compliance.

Over the years, extensive efforts have been expended on developingimproved injection methods and spring-powered autoinjectors. Mostautoinjectors have used a compression spring to power the expulsion ofmedication from a syringe. Another method that has been proposed for forpowering an autoinjector is the use of a torsion spring. For example,Karlsson in U.S. Pat. No. 8,702,660 describe an autoinjector in which atorsion spring inside the autoinjector can be tensioned by the user bymeans of a tensioning wheel to deliver a desired dose. The torsionspring applies force to a drive nut that is engaged with threads of aplunger rod. The plunger rod then expels medication through the needle.

Ekman et al. in U.S. Published Patent Application No. 20130123697describes an autoinjector with a torsion spring that is used forinserting the needle, emptying the syringe and then retracting theneedle and syringe. The autoinjector is activated by pressing a triggerbutton that releases the torsion spring to exert a force on a stopperand syringe. Eckman et al. report that the lead screw thread has avariable pitch arranged to advance a second gear member faster and withless force when inserting the needle (steep pitch) and more slowly withincreased force while expelling the medicament in the syringe.

Cowe in WO/2012/038721 describes a reusable autoinjector that can berewound and reused. Cowe also provides a rotary energy source such as atorsion spring. The disclosure is primarily directed to a constant pitchscrew thread, although Cowe mentions the possibility of a nonuniformpitch to provide a desired variable force profile.

Adams et al. in U.S. Pat. No. 8,734,394 describes an autoinjector thatuses a helically coiled wire to perform delay and needle retractionfunctions. The spring, referred to as a dual functioning biasing member,performs these two tasks independently and sequentially, first inrotation turning a component immersed in a damping fluid to achieve aprescribed delay time, and second in extension to retract the syringeand needle subassembly.

Despite these and other efforts, there remains a need to developinjection methods and autoinjectors with improved characteristics suchas relatively simpler or more compact design, smoother injection, and/orless noise.

SUMMARY OF THE INVENTION

The primary problem with spring-loaded autoinjectors is that either theinitial force is too great or the force at the latter stages of theinjection are too weak. We have developed a simple and elegant solutionto this problem by utilizing a spring in a manner that tailors therelease of energy as the spring is extended. The spring first advancesthe syringe and needle forward in a controlled manner with the objectiveof minimizing needle insertion force. The spring subsequently deliversthe medicament using a higher force with a profile tailored to suitoptimum delivery. One embodiment utilizes a nearly constant deliveryforce profile that stands in contrast to the decreasing force profile ofconventional coil springs.

Advantages of various embodiments of the invention include one or acombination of: reduced initial force during needle insertion andcorrespondingly less noise and less shock to the patient; reduced suddenimpact to the syringe and reduced chance of breakage; reduced suddenacceleration of the viscous medicine within the syringe and needle; theability to tailor flow for greater patient comfort and/or desiredinjection profile; reduced injection time; and/or less tissue disruptionor trauma at injection site.

In a first aspect, the invention provides a method of injecting amedicament from a syringe, comprising: providing a driving force thatmoves a plunger down a syringe from a distal position toward a proximalposition; wherein a torsion spring is attached at a distal end to afirst surface and at a proximal end to a second surface; wherein thesecond surface moves with the plunger; wherein an early stage movementof the plunger toward the proximal position twists the torsion spring tostore energy in the spring; and, subsequently, at a later stage, as thedriving force continues to move the plunger toward the proximalposition, and the second surface moves with the plunger, the torsionspring rotates through a prescribed path to modify the driving forcemoving the plunger toward the proximal position. The path can beprescribed by the design of a plunger movement assembly (PMA) describedbelow in an aspect describing injector apparatus.

In some embodiments, the torsion spring is a combination torsion andcompression spring. The use of a combination torsion and compressionspring in the present invention provides numerous advantages includingreduced friction losses.

The invention may have one or any combination of the following features:wherein the combination torsion and compression spring is the onlysource of providing the driving force; wherein, during the later stage,the torsion spring is untwisted to enhance the driving force; wherein,once activated, the injection occurs without any power source other thanthe spring; wherein the early stage movement corresponds to an initialperiod of syringe motion in which the driving force is relatively low inorder to insert the needle into the patient's skin (for example betweenabout 5% to 50% of the maximum driving force and/or the average force(averaged either over the time of injection or the distance ofinjection) or between about 10% and about 40%, or between about 10% and30%, or between about 15% and 30%) and in preferred embodiments thisinitial period is from activation of the autoinjector to 5 ms or 50 msor 100 ms (milliseconds) after activation, or from 0 to 5 mm, or 0 to 10mm of plunger motion; or wherein during the initial phase the drivingforce is from 1 to 20 Newtons (N), or from 2 to 10 N, or from 3 to 7 N;or any combination of these; where potential torsion energy in thespring is increased over the first 50 or 100 ms after activation, orfrom 0 to 5 mm, or 0 to 10 mm, or from 0 to about 15 mm, or from about 0to 25 mm; wherein potential torsion energy in the spring reaches amaximum at about 10 mm and/or about 7 ms (or between 5 ms and 50 ms)after activation, or between about 5 and 50 mm, or between about 5 mmand 30 mm, or between about 5 mm to 20 mm after activation; or betweenabout 5% to about 40% of the full distance traveled during theinjection; wherein the potential torsion energy in the spring increasesat least 5 N·mm or at least 10 N·mm, or between 10 and 500 N·mm, orbetween 15 and 300 N·mm, or between 20 and 200 N·mm; wherein the springis preloaded with both torsion energy and compression energy; whereinthe initial potential compression energy is greater than the initialpotential torsion energy; wherein the potential compression energy inthe torsion spring decreases approximately linearly as a function ofplunger motion; or wherein, during the second half of the injection(either by time or by plunger motion) the percentage of potentialtorsion energy in the spring decreases at a rate faster than thepercentage of potential linear energy; or wherein, after the initialphase, the driving force increases rapidly, for example, increasing atleast 10 N or wherein driving force at least doubles or at leasttriples, over a distance of 5 mm, or 2 mm, or less, or between 0.1 to 3mm of plunger motion, or a time of 1 s or less or between 20 ms and 1 s,or between 5 ms and 500 ms; or any combination of these; wherein thelater stage movement defines an injection phase, and wherein the drivingforce is reduced by less than 50%, more preferably less than 40%, orless than 20% or between 10 and 40%, or between 5 and 30% during theinjection phase; or wherein the driving force is remains between 10 and200 N, or between 10 and 40 N, or between 20 and 80 N, or between 20 and40 N during the injection phase; wherein, from an activation stepthrough the end of the injection phase, the potential compression energyin the spring is reduced by at least 40%, or at least 50% or from 30% to90%; and/or wherein the first surface is an internal surface of thedistal end of an autoinjector housing.

The inventive methods may further comprise a retraction stage,subsequent to the later stage, in which the spring pulls the plunger inthe distal direction. In some preferred embodiments, the second surfaceis on a nut, the spring is attached to the nut and the prescribed pathis controlled by a screw having helical threads; the nut has a pin orpins that ride in the threads of the screw; wherein, during theretraction stage, the pin or pins ride in the threads in a distaldirection and wherein the spring provides a torque having a forcecomponent in the direction in which the pin or pins ride. In someembodiments, the spring is attached to a nut and the prescribed path iscontrolled by a screw having helical threads; wherein the nut has a pinor pins that ride in the threads of the screw; wherein the helicalthreads have a thread angle α that varies along the length of the screw(see FIG. 23). In some preferred embodiments, friction occurs betweenthe pin or pins and the screw, wherein during at least a portion of thelater phase, the spring supplies a torque that has a force componentperpendicular to length in the direction of the threads of the screw.This serves to reduce friction as compared to a compression-only spring.

In a related aspect, the invention provides a method of injecting amedicament from a syringe, comprising: providing a driving force thatinserts a needle at the proximal end of the device, then subsequentlymoves a plunger down a syringe from a distal position toward a proximalposition; wherein a spring having both a torsion mode and a compressionmode is attached at one end to a first surface and at one end to asecond surface; wherein the second surface moves with the plunger and anearly stage movement of the plunger toward the proximal position twiststhe torsion spring to store energy in the spring; and subsequently asthe driving force due to the compression mode continues to move theplunger toward the proximal position, and the second surface moves withthe plunger, the torsion mode of the spring rotates thru a prescribedpath to modify the driving force moving the plunger toward the proximalposition. In various preferred embodiments of this aspect, the insertionof the needle is accomplished by transferring energy from thecompression mode of the spring to the torsion mode spring in order tooptimize force needed for needle insertion; wherein the energy isreleased from the compression spring by changing the length of thespring and the energy is added to the torsion mode of the spring byincreasing the number of winds of the spring; where the coil spring wirehas a round cross section; where the coil spring wire has a square crosssection in order to increase the amount of stored energy possible in agiven package size; wherein the step in which the torsion mode of thespring rotates through a prescribed path to modify the driving forcecomprises untwisting the spring to release energy from the spring toenhance the driving force moving the plunger toward the proximalposition; and/or where the coil spring wire has a rectangular cross inorder to optimize the relationship of the compression and torsioncharacteristics of the spring.

In another aspect, the invention provides an injector apparatus,comprising: an elongate outer casing having a distal end and a proximalend; a plunger movement assembly (PMA), comprising:

(a) a screw axially disposed within the outer casing;

the screw having helical threads;

a nut wherein the nut has a pin or pins that ride in the threads of thescrew;

wherein the screw has external threads and the nut is disposed aroundthe screw; and

a combination compression and torsion spring that is connected at thedistal end to the casing and connected at the proximal end to the nut;

a plunger rod connected to the proximal end of the nut; or

(b) a nut comprising an axial central cylindrical orifice having helicalgrooves;

a screw flange disposed within the central cylindrical orifice having apin or pins that ride in the helical grooves;

a plunger rod connected to the screw flange; and

a combination compression and torsion spring that is connected at thedistal end to the casing and connected at the proximal end to the screwflange;

a syringe adapted for containing a medicament attached to the outercasing and/or a proximal end of the PMA; and wherein the proximal end ofthe plunger rod is slide-ably disposed within the syringe.

In various preferred aspects, the injector apparatus comprises one orany combination of the following features: the injector apparatus havingthe PMA of type (a) wherein the screw having helical threads comprisesthreads in a first portion that turn in a first direction, and that turnin a second direction in a second portion; and wherein the nut has a pinor pins that ride in the threads of the screw such that the nut turns inthe first direction in the first portion and in the opposite directionin the second portion (for example clockwise and counterclockwise); ahollow needle disposed at the proximal end of the syringe; an injectorhaving the PMA of type (b) wherein the nut having helical groovescomprises grooves in a first portion that turn in a first direction, andthat turn in a second direction in a second portion; and wherein thescrew flange has a pin or pins that ride in the grooves of the nut suchthat the screw flange turns in the first direction in the first portionand in the opposite direction in the second portion (for exampleclockwise and counterclockwise); wherein the first portion is nearer thedistal end and the second portion is nearer the proximal end; whereinthe proximal tip of the plunger rod is rotatably disposed within aplunger cap; wherein the proximal end of the plunger rod is rotatablydisposed within a plunger cap by a jewel bearing; wherein the plungerrod has a proximal tip 71 that abuts a surface of the plunger cap and arestricted neck portion 71 a; and wherein the plunger cap has a distalend having flanges that project inwardly toward the central axis;wherein a syringe carrier retains the syringe within a housing; whereinin the first portion, the screw angle is in the range of −70 to −20degrees, in some embodiments from −60 to −30 degrees; then for thesecond portion, the screw angle is positive, in some embodiments 10degrees or more, in some embodiments in the range between 10 and 80degrees; wherein in the first portion, the screw's lead is negative andin some embodiments is between 10 and 120 mm, in some embodimentsbetween 20 and 80 mm, or between 30 and 70 mm; wherein the leaddecreases during the first portion, in some preferred embodiments, thisdecrease is approximately monotonic, preferably with a decrease of about5 mm to about 40 mm; wherein in the second portion the screw lead ispositive for at least a portion of the injection, preferably for theentire injection, and is preferably between 2 and 500 mm, in someembodiments between 10 and 300 mm, or between 15 and 200 mm; in someembodiments, the lead decreases during the second portion, in somepreferred embodiments, this decrease is approximately monotonic,preferably with an decrease of at least about 20 mm or at least about 50mm, or in the range of about 20 mm to about 300 mm, or 10 mm to 150 mmover the length of the second portion; and/or wherein the screw leaddecreases during the second portion from about 170±40 mm to about 20±40mm over the length of the second portion. In a preferred embodiment, thehelical threads have a first direction at the distal end and the springhas a wind direction which is opposite that of the first direction. Thisconfiguration can be advantageous for securing the ends of the spring.

In a preferred embodiment, the helical threads have a first direction atthe distal end; and, at the proximal end, have threads having a seconddirection that causes the needle to move in the distal direction therebycausing the needle to retract and lock into a stored location.

In another aspect, the invention provides a method of injecting amedicament from a syringe, comprising: providing a driving force thatmoves a plunger along an axis from a distal position toward a proximalposition down a syringe; wherein a combination compression and torsionspring is attached at a distal end to a first surface and at a proximalend to a second surface; wherein the second surface moves with theplunger; wherein the second surface is on a nut such that the spring isattached to the nut; wherein the nut has a pin or pins that ride in thethreads of a screw having helical threads; wherein the spring provides atorque having a force component that is perpendicular to the axis and isin a direction in which the pin or pins ride toward the proximalposition; wherein the combination of the energy stored in compressionand torsion is released in a prescribed manner based on the distancebetween the distal and proximal positions. The first surface istypically on the housing of an autoinjector.

In many cases, the invention does not require features such as: asecondary compression spring for tasks such as needle insertion; aviscous damping fluid to reduce insertion speed; operation inconjunction with a pressurized gas; however, in some aspects, theinvention may utilize one or more of these features.

Glossary

A torsion spring is an elastic object that stores mechanical energy whenit is twisted. A preferred form of a torsion spring is a helical wire. Acompression spring stores energy when compressed and then releases thatenergy when the spring is released, and is preferably in the form of ahelical wire. An extension spring is an elastic material (typically ahelical spring) that stores energy when extended and releases thatenergy when the spring is released.

A compression spring is defined as a spring that, in its first releasedstate, can be compressed by at least 10% (preferably at least 50%) andagain released to recover at least 95% (preferably at least 99%) of itslength in the first released state. A torsion spring, according to thepresent invention, in its relaxed state can be twisted at least about90° (quarter twist), more preferably at least a half twist, or in someembodiments at least a full twist, or between a quarter and a fulltwist, and then return to its initial position. A combinationcompression and torsion spring has the properties of both a compressionspring and a torsion spring.

A medicament is also called a medicine.

The “driving force” is the axial force along the vector from the distalend to the proximal end that expels the medicine from the syringe(typically a conventional cylindrical syringe); and, typically, alsopushes the needle through the skin of the patient.

A “jewel bearing” is a bearing in which an end of a plunger rod rotatesfreely without roller bearings.

The proximal end is the end of the device near the point where theneedle enters the patient while the distal end is the opposite end thatis furthest from the patient.

The first surface can be an inner surface of an enclosure which istypically an elongated container; alternatively it can be a stopper orany solid component (typically fixed in place) disposed within acontainer. The distal end of the torsion spring can be attached to thefirst surface by lodging the end within a notch or attachment mechanismthat adheres the torsion spring to the first surface. The second surfaceis typically the distal end of a nut or plunger rod.

Various aspects of the invention are described using the term“comprising;” however, in narrower embodiments, the invention mayalternatively be described using the terms “consisting essentially of”or, more narrowly, “consisting of.”

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an exploded side view of an autoinjector.

FIG. 2A illustrates device activation. FIG. 2B illustrates anon-exploded side view of the autoinjector of FIG. 1.

FIG. 3 is a schematic cross-sectional view of an autoinjector having acentral, fixed screw.

FIG. 4A illustrates a cross sectional view of an autoinjector. FIG. 4Billustrates an external view of an autoinjector.

FIG. 5 is a schematic cross-sectional view of a jewel bearing thatprovides for low friction rotation of a plunger within a syringe.

FIG. 6 illustrates a nut that rides down a fixed screw.

FIG. 7 illustrates a fixed screw having grooves in which pins on a nutride down the screw.

FIG. 8 illustrates a plunger.

FIG. 9 illustrates motion of a nut riding down a screw.

FIG. 10 is a schematic cross-sectional view of an autoinjector prior toactivation.

FIG. 11 is a schematic cross-sectional view of an autoinjector priorafter activation.

FIG. 12 illustrates an exploded view of a release button.

FIG. 13 is an exemplary plot of force versus plunger motion.

FIG. 14 is an exemplary plot of work out, potential energy of the spring(compression and torsion components) and friction loss.

FIG. 15 is an exemplary plot of screw angle (also known as thread angle)versus plunger motion.

FIG. 16 is an exemplary plot of screw lead (axial travel for a singlerevolution) versus plunger motion.

FIG. 17A shows a view of the screw with regions for needle insertion,fluid delivery, and needle retraction. FIG. 17B is a view showing threadgrooves around the central axis.

FIG. 18 shows force and energy as a function of plunger motion duringinsertion, delivery and retraction.

FIG. 19 shows the relationship between thread (screw) angle and plungermotion.

FIG. 20 shows the end of a plunger with a plunger cap.

FIGS. 21-22 compare the measured force output (in N) versus distance ofplunger rod travel for 25N and 50N combination compression/torsionsprings used in the present invention and the same force springs usedonly in compression.

FIGS. 23-25 show geometry and forces of a free body analysis of apreferred embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

FIGS. 1, 2, 4, 5, and 12 illustrate one embodiment of the invention. Tooperate the device, the user will typically remove it from packaging andallow it to equilibrate to room temperature if stored refrigerated. Asterile needle shield cover would be removed (not shown) to expose theneedle. To use the device the user would first prepare the injectionsite (e.g., abdomen, thigh, arm) and locate the proximal end of thedevice against the injection site. To operate the device, the user turnsthe unlock collar. Turning (step 1 in FIG. 2A) the unlock collar 10lifts the lock plate 12 using ramps 10 a so the keyway 12 a on the lockplate exits the key on the plunger screw 14 a that includes screw flange15. Turning the unlock collar also rotates the button 16 which moves thebottom of the button 16 b away from the support ledge 20 a and allows itto move freely in the axial direction. In this state, the device isunlocked, but will not actuate. To actuate the device, the userdepresses the button 16 (step 2 in FIG. 2A). The ramps 16 a on thebutton cause the plunger screw to rotate. The plunger screw 14 thentravels both axially and rotationally down the nut due to both the forceand torque applied by the drive spring 22. The initial portion of themovement inserts the needle into the patient's skin to the proper depth.After this depth is achieved, the remainder of the movement expels druginto the patient. Optionally, a needle retraction feature (discussedbelow) and safety lockout mechanism (not shown) could be added so thatthe device could be safely disposed of after use.

The device additionally comprises casing 18, which, in the illustratedembodiment, includes sleeve 20 and button 16 and lock plate 12. Theinvention is sometimes described as having a spring 22 connected to thesleeve 20; this means that the spring is either directly attached to thesleeve or attached to a stationary structure (such as an internalflange) that is, in turn, connected to the sleeve. The casing surroundsthe sleeve which can be split into multiple pieces for improvedmanufacturability. Tabs 25 on the spring can be passed through holes ina suitable structure such as flange 27 and movable nut 29.

FIG. 4 shows an outer view (right side) and cross-sectional view (leftside) of a portion of an injector including a nut 42 having grooves 44that include an upper (first) portion having a relatively steep groove46 in a direction that cooperates with screw flange 15 to slow theplunger 48 and store energy in torsion spring 50. At location 52, a kneein the groove reverses the twist direction of the torsion spring. In thelower (second) portion 54, the torsion spring untwists and releasesenergy into the spring to maintain a constant or nearly constant forcethat pushes the plunger into the syringe and thus maintains a constantflow of medicine out of the syringe throughout the injection. Therelease of energy is further aided by controlling the angles of thethread in the lower portion. The screw flange 15, plunger rod 48,torsion (or typically combination torsion and compression) spring 50,and nut 42 form a plunger movement assembly 62. Because the plungerscrew 14 is rotated, it is desirable to have a bearing 64 to facilitaterotation of the plunger rod within the syringe 58. Another possibilityis to place a bearing between the plunger rod and the screw flange.

A schematic illustration of a bearing assembly 66 is shown in FIG. 5.The plunger rod 48 terminates at the proximal end in a knob 68. A jewelbearing 71 is formed by the knob disposed in cage 72 having asufficiently large inner diameter to allow the presence of a small space74 between the knob and the cage allowing the plunger rod to rotatefreely while also translating down the axis of the syringe 76, and thelower surface 78 of the cage effectively forms the bottom surface of theplunger at the point in which plunger and medicament 80 in the syringecontact each other. An upper flange 82 on the syringe within clamp 84forms a seal and maintains the connection between the syringe and theplunger rod 48 and also plunger movement assembly 62.

A drawing of a preferred embodiment of the inventive injector apparatusis illustrated in FIGS. 3 and 6-11. An elongated housing 102 contains acombination torsion and compression spring 22, a threaded screw 104, asyringe carrier 111, a nut 106 disposed around the screw, a plunger rod108, and a syringe 110. In operation, the syringe includes a hollowneedle (not shown) affixed to the proximal end of the syringe. Thehousing should be rigid enough to withstand a person gripping thehousing without substantial deformation that would inhibit springaction. The illustrated housing only partly encloses the syringe;however, the housing could alternatively be extended to enclose thesyringe and, optionally, the needle. In another alternative, the entiredevice could be disposed within a larger housing unit (not shown). Thecombination torsion and compression spring is disposed about the screwand is affixed at the distal end to the housing and at the proximal endto the nut. Prior to injection, the spring is held in place by a springstop. For operation, the user will press a button or activate a lever,etc. (not shown) to move the spring stop and release the spring. The key112 on the plunger rod allows the syringe to be supported prior toactivation so that the needle does not protrude from the device beforethe user begins an injection. During storage, the key keeps itrotationally aligned with the body of the device. The nut has agenerally cylindrical shape and a pair of projections 114 that ride inthe threads of the screw. The spring propels the nut down the shaft ofthe screw. The screw is fixed within the housing, typically by a flange116 that is affixed to the distal end of the housing. The screw has aknee 118 at that reverses the direction of the nut as it rides down thescrew. In preferred embodiments, as the nut initially rides down thescrew, the threads 120 are very steep so that the needle advances in acontrolled manner with a relatively small force. The threads cause thenut to rotate in a direction to twist and thus store additionaltorsional energy in the spring. Once the needle is fully advanced, thedriving force increases rapidly. In the initial phase the compressionforce from the spring is at its highest, then as the plunger continuesto advance in the proximal direction, the compression force availablefrom the spring drops and, after the nut passes the knee in the screw,the spring untwists and torsion energy is released causing an increasein the driving force pushing the plunger in the proximal direction.

The nut can be physically attached to the plunger rod or could pressagainst the plunger rod (either directly or through an interveningcomponent). In the illustrated embodiment, clip 124 secures flange 126on the plunger 108. The motion of the nut pushes the plunger rod, which,in an initial stage pushes the syringe forward in the housing to advancethe needle into the patient. The syringe could be held by a slidabledisk that slides within the housing it is reaches a stop. Once thesyringe is stopped, the plunger pushes medicine out of the syringethrough the needle. The plunger rod is rigid, cylindrical and disposedabout the screw.

In another alternative embodiment, the user can twist the spring andthus control the initial extent of torsional energy stored in the springat the start of injection.

The selection of materials for the injector device can be selected bythe skilled engineer. In some embodiments, a lubricant (such as siliconeoil) is disposed between surfaces that slide over each other duringoperation.

The medicine within the syringe could be any solution or suspension; butthe invention is especially advantageous for the delivery of a liquidhaving an absolute viscosity greater than 20 cP. Absolute viscosity canbe measured by capillary rheometer, cone and plate rheometer, or anyother known method. Preferably, the viscous solution comprises a proteinsuspension. Exemplary plots of force versus plunger motion that arewithin the scope of the present invention are shown in FIG. 13. Theinvention includes force and/or work versus motion profiles thatcorrelate with any of the plots described herein, either qualitativelyor within 20% (or within 10%) of the values shown here. For example, theinvention includes methods of injecting a medicament from a syringepossessing one or any combination of the following characteristics: aninitial period of syringe motion in which the driving force isrelatively low in order to insert the needle into the patient's skin(for example between about 5% to 50% of the maximum driving force and/orthe average force (averaged either over the time of injection or thedistance of injection) or between about 10% and about 40%, or betweenabout 10% and 30%, or between about 15% and 30%) and in preferredembodiments this initial period is from activation of the autoinjectorto 50 or 100 ms (milliseconds) after activation (or within the range of5 ms to 50 ms), or from 0 to 5 mm, or 0 to 10 mm of plunger motion; or aspeed of 200 mm/s to 4000 mm/s during the insertion; wherein during theinitial phase the driving force is from 1 to 20 Newtons (N), or from 2to 10 N, or from 3 to 7 N; where potential torsion energy in the springis increased over the first 50 or 100 ms after activation, or from 0 to5 mm, or 0 to 10 mm, or from 0 to about 15 mm, or from about 0 to 25 mm;wherein potential torsion energy in the spring reaches a maximum ofabout 10 mm and about 7 ms (or between 5 ms and 50 ms) after activation,or between about 5 and 50 mm, or between about 5 mm and 30 mm, orbetween about 5 mm to 20 mm after activation; or between about 5% toabout 40% of the full distance traveled during the injection; whereinthe potential torsion energy in the spring increases at least 5 N·mm orat least 10 N·mm, or between 10 and 500 N·mm, or between 15 and 300N·mm, or between 20 and 200 N·mm; wherein the spring is preloaded withboth torsion energy and compression energy; wherein the initialpotential compression energy is greater than the initial potentialtorsion energy; wherein the potential compression energy decreasesapproximately linearly as a function of plunger motion; wherein, duringthe second half of the injection (either by time or by plunger motion)the percentage of potential torsion energy in the spring decreases at arate faster than the percentage of potential linear energy; wherein,after the initial phase, the driving force increases rapidly, forexample, increasing at least 10 N or wherein driving force at leastdoubles or at least triples, over a distance of 5 mm, or 2 mm, or less,or between 0.1 to 3 mm of plunger motion, or a time of 1 s or less orbetween 20 ms and 1 s, or between 30 ms and 500 ms; wherein the drivingforce is reduced by less than 50%, more preferably less than 40%, insome embodiments less than 20% and in some embodiments between 10 and40%, or 5 and 30% during the injection phase; wherein the driving forceis remains between 10 and 200 N, or between 10 and 40 N, or between 20and 80 N, or between 20 and 40 N during the injection phase; andwherein, from the activation step through the end of the injectionphase, the potential compression energy in the spring is reduced by atleast 40%, or at least 50% or from 30% to 90%.

An exemplary plot of work out in a preferred embodiment is shown in FIG.14. As can be seen, after an initial stage, work out as a function oflength is linear (derivation of slope is zero). Potential energy of thespring (compression and torsion components) and friction loss.

An exemplary plot of screw angle (also known as thread angle) versusplunger motion, that is within the scope of the present invention, isshown in FIG. 15. An exemplary plot of screw lead (axial travel for asingle revolution) versus plunger motion, that is within the scope ofthe present invention, is shown in FIG. 16. These plots are not limitingbut show examples of the characteristics of some preferred embodimentsof the invention. In some preferred embodiments of the invention, in theinitial phase, the screw angle is in the range of −70 to −20 degrees, insome embodiments from −60 to −30 degrees; then for the second(injection) phase, the screw angle is positive, in some embodiments 10degrees or more, in some embodiments in the range between 10 and 80degrees. In some preferred embodiments of the invention, in the initialphase, the screw's lead is negative and in some embodiments is between10 and 120 mm, in some embodiments between 20 and 80 mm, or between 30and 70 mm; in some embodiments, the lead decreases during the initialphase, in some preferred embodiments, this decrease is approximatelymonotonic, preferably with a decrease of about 5 mm to about 40 mm; thenfor the second (injection) phase, the screw lead is positive for atleast a portion of the injection, preferably for the entire injection,and is preferably between 2 and 500 mm, in some embodiments between 10and 300 mm, or between 15 and 200 mm; in some embodiments, the leaddecreases during the second phase, in some preferred embodiments, thisdecrease is approximately monotonic, preferably with an decrease of atleast about 20 mm or at least about 50 mm, or in the range of about 20mm to about 300 mm, or 10 mm to 150 mm over the length of the secondphase. In some embodiments, the lead decreases during the second phasefrom about 170±40 mm to about 20±40 mm over the length of the secondphase. The second phase refers to the injection phase.

Retraction Load Path

An example of a reversing thread path and corresponding plots of forceversus plunger motion, and screw angle versus plunger motion are shownin FIGS. 17-20. As described above, there is an initial portion forneedle insertion 171, and a fluid delivery portion 173 where the threadpath provides for relatively constant force during the course of theinjection. In the illustrated embodiment, a reversing thread path 175(needle retract) is added to provide for needle retraction at the end ofthe injection. During the retraction, the screw angle and force becomenegative; the nut reverses course and moves toward the distal end of theinjector. Since there is no hydraulic load in the reverse direction, theplunger screw quickly retracts. The nut, foot, and syringe carrier allmove in the distal direction on retraction. As shown in FIG. 20, theproximal end of the plunger has a foot 201, thread 203 and piston cap205 that fits tightly within the syringe barrel 207. The frictionbetween the plunger and the syringe barrel is typically much greaterthan the friction to withdraw the needle from the skin which causes thesyringe to move in the reverse direction with the piston. As the syringeis withdrawn, the pressure within the syringe is quickly relieved fromthe syringe contents which stops delivery of fluid. At the end of theretraction, the torsion spring could lock the mechanism into arotational detent position, thus locking the syringe in the retractedstate.

Test Data

The combination compression/torsion spring was tested in conjunctionwith a plunger screw, nut and roller bearings. FIGS. 21-22 compare themeasured force output (in N) versus distance of plunger rod travel forthe combination compression/torsion springs used in the presentinvention and the same springs used only in compression. As can be seen,for both 25 N and 50 N springs, the combination compression/torsionsprings used in the present invention provide greater and more constantforce over the length of the simulated injection. The inventiveconfiguration provided a near plateau, with less than a 20% decrease inforce over the length of a simulated injection while the straightcompression spring shows about a 50% decrease in force over the lengthof the simulated injection. As a result, the inventive configurationwill provide a faster, smoother, and/or more complete injection ascompared with a device powered by a conventional compression spring.

A free body diagram analysis is useful for determining forces, torquesand friction loads on the autoinjector mechanism based on thecharacteristics of the geometry (i.e. radius, thread pitch, etc.) Bytaking each component and examining the applied forces and torques ateach physical interface, a mathematical relationship can be developed.From these equations, the characteristics can be explored and the designcan be adjusted to achieve the desired results. The free body analysispresented below was used to develop the theoretical performance curvespresented in FIGS. 13 thru 16 based on a preferred embodiment. FIGS. 23thru 25 show the preferred ranges of forces, torques, energy and screwgeometry.

In some instances, preferred embodiments of the invention can becharacterized by the following geometry including a threaded screw andthe corresponding equations:

The following list of terms relates to the embodiment having the type ofgeometry illustrated in FIG. A-C.

F_(s)=force applied by spring

T_(s)=torque applied by spring

F_(T)=force on thread

R_(T)=radius of thread

μ_(T)=friction coefficient of thread

α=angle of thread

F_(B)=force on bearing

R_(B)=radius of bearing

μ_(B)=friction coefficient of bearing

F_(K)=force on key

R_(K)=radius of key

μ_(k)=friction coefficient of key

F_(out)=force output

The various forces and torques in the autoinjector can be understoodusing free body diagrams as follows:Free body diagram of the Nut:Sum of forces in the Y direction must equal zero:

(μ_(T) F _(T))cos α−F _(T) sin α+F _(B) —F _(s)=0

F _(T)=(F _(s) −F _(B))/((μ_(T))cos α−sin α)

Sum of torques must equal zero:

T _(s)−(μ_(T) F _(T) R _(T))sin α−(F _(T) R _(T))cos α−μ_(B) F _(B) R_(B)=0

T _(s) =F _(T) R _(T)((μ_(T))sin α+cos α)+μ_(B) F _(B) R _(B)

Combining forces and torques:

T _(s) =R _(T)(F _(s) −F _(B))/(((μ_(T))sin α+cos α)/((μ_(T))cos α−sinα))+μ_(B) F _(B) R _(B)

β=((μ_(T))sin α+cos α)/((μ_(T))cos α−sin α)=((μ_(T))Tan α+1)/(μ_(T)−Tanα)

F _(B)=(T _(s) −R _(T) F _(s)β)/(μ_(B) R _(B) −R _(T)β)

Free Body Diagram of the plunger rod:Sum of torques must equal zero:

μ_(B) F _(B) R _(B) =F _(K) R _(K)

F _(K)=μ_(B) F _(B) R _(B) /R _(K)

Sum of forces must equal zero:

F _(out) =F _(B)−μ_(K) F _(K)

Combining forces and torques:

F _(out) =F _(B)(1−μ_(K)μ_(B) R _(B) /R _(K))

In some embodiments, the inventive methods and apparatus may becharacterized by full or partial conformance with the features describedin the forgoing free body analysis.

1. A method of injecting a medicament from a syringe, comprising:providing a driving force that moves a plunger down a syringe from adistal position toward a proximal position; wherein a torsion spring isattached at a distal end to a first surface and at a proximal end to asecond surface; wherein the second surface moves with the plunger;wherein an early stage movement of the plunger toward the proximalposition twists the torsion spring to store energy in the spring; and,subsequently, at a later stage, as the driving force continues to movethe plunger toward the proximal position, and the second surface moveswith the plunger, the torsion spring rotates through a prescribed pathto modify the driving force moving the plunger toward the proximalposition.
 2. The method of claim 1 wherein the torsion spring is acombination torsion and compression spring.
 3. The method of claim 2wherein the combination torsion and compression spring is the onlysource of providing the driving force.
 4. The method of claim 2 wherein,during the later stage, the torsion spring is untwisted to enhance thedriving force.
 5. The method of claim 2 wherein, once activated, theinjection occurs without any power source other than the spring.
 6. Themethod of claim 2 wherein the early stage movement corresponds to aninitial period of syringe motion in which the driving force isrelatively low in order to insert the needle into the patient's skinthis initial period is from activation of the autoinjector to 50 or 100ms (milliseconds) after activation, or from 0 to 5 mm, or 0 to 10 mm ofplunger motion; or wherein during the initial phase the driving force isfrom 1 to 20 Newtons (N), or from 2 to 10 N, or from 3 to 7 N.
 7. Themethod of claim 2 where potential torsion energy in the spring isincreased over the first 50 ms after activation; wherein potentialtorsion energy in the spring reaches a maximum between about 10 ms andabout 1 s after activation, or between about 5 and 50 mm afteractivation; or between about 5% to about 40% of the full distancetraveled during the injection; wherein the potential torsion energy inthe spring increases at least 5 N·mm.
 8. The method of claim 2 whereinthe spring is preloaded with both torsion energy and compression energy.9. The method of claim 8 wherein the initial potential compressionenergy is greater than the initial potential torsion energy.
 10. Themethod of claim 2 wherein the potential compression energy in thetorsion spring decreases approximately linearly as a function of plungermotion; or wherein, during the second half of the injection (either bytime or by plunger motion) the percentage of potential torsion energy inthe spring decreases at a rate faster than the percentage of potentiallinear energy; or wherein, after the initial phase, the driving forceincreases rapidly, for example, increasing at least 10 N or whereindriving force at least doubles or at least triples, over a distance of 5mm, or 2 mm, or less, or between 0.1 to 3 mm of plunger motion, or atime of 1 s or less or between 20 ms and 1 s, or between 30 ms and 500ms; or any combination of these.
 11. The method of claim 2 wherein thelater stage movement defines an injection phase, and wherein the drivingforce is reduced by less than 50%, more preferably less than 40%, orless than 20% or between 10 and 40%, or between 5 and 30% during theinjection phase; or wherein the driving force is remains between 10 and200 N, or between 10 and 40 N, or between 20 and 80 N, or between 20 and40 N during the injection phase.
 12. The method of claim 2 wherein, froman activation step through the end of the injection phase, the potentialcompression energy in the spring is reduced by at least 40%, or at least50% or from 30% to 90%.
 13. The method of claim 3 further comprising aretraction stage, subsequent to the later stage, in which the springpulls the plunger in the distal direction.
 14. The method of claim 13wherein the second surface is on a nut, wherein the spring is attachedto the nut and wherein the prescribed path is controlled by a screwhaving helical threads; wherein the nut has a pin or pins that ride inthe threads of the screw; wherein, during the retraction stage, the pinor pins ride in the threads in a distal direction and wherein the springprovides a torque having a force component in the direction in which thepin or pins ride.
 15. The method of claim 1 wherein the spring isattached to a nut and wherein the prescribed path is controlled by ascrew having helical threads; wherein the nut has a pin or pins thatride in the threads of the screw; wherein the helical threads have athread angle α that varies along the length of the screw. 16-32.(canceled)
 33. A method of injecting a medicament from a syringe,comprising: providing a driving force that inserts a needle at theproximal end of the device, then subsequently moves a plunger down asyringe from a distal position toward a proximal position; wherein aspring having both a torsion mode and a compression mode is attached atone end to a first surface and at one end to a second surface; whereinthe second surface moves with the plunger and an early stage movement ofthe plunger toward the proximal position twists the torsion spring tostore energy in the spring; and subsequently as the driving force due tothe compression mode continues to move the plunger toward the proximalposition, and the second surface moves with the plunger, the torsionmode of the spring rotates thru a prescribed path to modify the drivingforce moving the plunger toward the proximal position.
 34. The method ofclaim 33 wherein the insertion of the needle is accomplished bytransferring energy from the compression mode of the spring to thetorsion mode spring in order to optimize force needed for needleinsertion. 35-36. (canceled)
 37. The method of claim 33 where the coilspring wire has a square cross section.
 38. The method of claim 33wherein the step in which the torsion mode of the spring rotates througha prescribed path to modify the driving force comprises untwisting thespring to release energy from the spring to enhance the driving forcemoving the plunger toward the proximal position. 39-40. (canceled)